Growth promotion

ABSTRACT

β-Phenethanolamines are effective in promoting growth and improving feed efficiency and leanness in animals.

This application is a continuation of application Ser. No. 07/606,670,filed Oct. 31, 1990, now abandoned which was a division of Ser. No.07/328,996, filed Mar. 27, 1989, U.S. Pat. No. 4,992,473 which was adivision of Ser. No. 07/153,640, filed Feb. 8, 1988, U.S. Pat. No.4,849,453, which was a division of Ser. No. 06/860,719, filed May 7,1986, U.S. Pat. No. 4,734,437, which was a continuation of Ser. No.06/628,002, filed Jul. 5, 1984, now abandoned, which was a continuationof Ser. No. 06/462,587, filed Jan. 31, 1983, now abandoned.

BACKGROUND OF THE INVENTION

The chemistry and use of β-phenethanolamines has been extensivelyinvestigated. A number of these compounds have been reported to havebeneficial cardiac activities; see U.S. Pat. No. 3,987,200. Suchcompounds also are known to have sympathomimetic activity, and havefound utility as utero-relaxing agents; Van Dijk et al., Recueil, 92,1281 (1973). More recently, a group of β-phenethanolamines have beenreported as possessing anti-hyperglycemic activity, and have been foundeffective in promoting the loss of weight in animals, EPO 6735 publishedJan. 9, 1980.

An object of this invention is to provide a new use for certainβ-phenethanolamines. This invention provides a method for promoting thegrowth of domesticated animals employing β-phenethanolamines.

SUMMARY OF THE INVENTION

This invention provides a method for increasing weight gain in animalsand improving the efficiency of feed utilization and the quality of thecarcass. The invention is more particularly directed to a method forpromoting growth and improving feed efficiency and leanness comprisingadministering an effective amount of a compound having the formula##STR1## wherein: R¹ is hydrogen, hydroxy, or methoxy;

R² is hydrogen or fluoro,

R³ is hydrogen or C₁ -C₂ alkyl;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen, fluoro, nitro, hydroxy, SO₂ CH₃ or CONH₂ ; provided thatR¹ is hydrogen only when R⁵ is nitro or SO₂ CH₃ ; and the acid additionsalts thereof.

A preferred method for promoting growth and improving feed efficency andleanness according to this invention employs a compound of the aboveformula wherein R¹ is hydroxy, R² is hydrogen, R³ is hydrogen or methyland R⁴ is methyl. The method is most preferably practiced employing acompound wherein R¹ and R⁵ both are hydroxy and R² and R³ both arehydrogen and R⁴ is methyl. When R¹ is hydroxy or methoxy, it preferablyis in the para position. When R⁵ is other than hydrogen, it also ispreferably in the para position.

This invention also provides an animal feedstuff comprising aβ-phenethanolamine of the above formula together with a suitable carriertherefor.

DETAILED DESCRIPTION OF THE INVENTION

The compounds employed in the method provided by this invention areeither known in the art or are readily prepared by well known syntheticprocedures. A particularly preferred method employs1-(3-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol.This β-phenethanolamine is disclosed in South African Patent No. 673,994published in May, 1967. The most preferred embodiment of this inventionemploys1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)-propylamino]ethanol,a compound disclosed as having utero-relaxing, activity by Van Dijk etal. in Recueil, 92 1281 (1973).

The compounds to be employed in the method of this invention are readilyprepared by reaction of a styrene oxide with a 3-phenylpropylaminederivative. For example, a styrene oxide such as 2-fluorostyrene oxidecan be reacted with about an equimolar quantity of an amine such as1-methyl-3-(4-nitrophenyl)propylamine in an unreactive organic solventsuch as ethanol, methanol, n-propanol, dioxane, or the like. Thereaction generally is carried out at a temperature of about 50° to about120° C., and at such temperature the reaction routinely is substantiallycomplete within about 6 to about 10 hours. The product, aβ-phenethanolamine, is readily isolated by simply removing the reactionsolvent, for instance by evaporation under reduced pressure, and furtherpurification can be accomplished if desired by standard techniques,including crystallization, chromatography, acid-base extraction, and thelike.

An alternative method for preparing the β-phenethanolamines to beemployed in the present method comprises reacting a mandelic acidderivative with a 3-phenylpropylamine derivative to provide an amide,which upon subsequent reduction provides a compound of the aboveformula. For example, a phenylpropylamine derivative such as1-methyl-3-(3-fluorophenyl)propylamine can be reacted with an acylatingagent such as a hydroxy protected mandelic acid halide, or preferablysimply reacted with a mandelic acid in the presence of a common peptidecoupling reagent such as N,N'-dicyclohexylcarbodiimide,carbonyldiimidazole, N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline,commonly referred to as EEDQ. The direct coupling reaction generally isconducted in an organic solvent such as benzene orN,N'-dimethylformamide, and normally is complete after about 2 to 48hours when carried out at about -30° to about 100° C. The product is anamide that is readily isolated by simply filtering the reaction mixtureand then removing the reaction solvent. The amide thus formed is nextreduced by reaction with a common reducing agent such as diborane or thelike to provide a β-phenethanolamine defined by the above formula.

A similar, yet alternative, method of synthesis comprises reacting aphenethanolamine with a phenylethyl ketone to provide a Schiff base,which upon reduction gives a compound to be employed in the presentmethod. For example, a phenethanolamine such as2-hydroxy-2-(4-hydroxyphenyl)ethylamine can be reacted with a ketonesuch as methyl 2-(4-hydroxyphenyl)ethyl ketone to provide thecorresponding imine, which upon reduction, for instance with 5%palladium on carbon, provides1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol.

It should be noted that the compounds to be employed in the method ofthis invention possess at least one asymmetric center (i.e. the carbinolcenter), and when R³ and R⁴ differ, the compounds possess two asymmetriccenters. Since employment of individual optical isomers necessitatespreparing the β-phenethanolamines from optically active startingmaterials, or using costly separation procedures, a preferred embodimentof this invention employs a mixture of optical isomers. For example,1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolis preferably prepared from racemic mixtures of starting materials, e.g.d1-1-methyl-3-(4-hydroxyphenyl)propylamine and d1-4-hydroxystyreneoxide, to provide a mixture of all four possible optical isomers of theproduct. The mixture of optical isomers is employed in the methodwithout subsequent separation of isomers.

Since the β-phenethanolamines to be employed in the present method areinherently basic, they readily form acid addition salts with any numberof inorganic and organic acids. These salts can be employed in themethod of the invention, and often are preferred to the free base sincethey generally are more soluble in solvents such as water and are moreconveniently formulated as an animal feedstuff. Acids commonly employedto form acid addition salts include mineral acids such as hydrochloricacid, sulfuric acid, phosphoric acid, perchloric acid and the like; andorganic acids such as acetic acid, citric acid, succinic acid,para-toluene sulfonic acid, methanesulfonic acid, lactic acid and thelike. Preferred salts to be employed in the present method include thehydrochlorides and hydrobromides.

Typical β-phenethanolamines to be employed in the method of thisinvention include the following:

1-(3-hydroxyphenyl)-2-[1-methyl-1-ethyl-3-(4-aminocarbonylphenyl)propylamino]ethanol;

1-(2-fluoro-4-hydroxyphenyl)-2-[1-methyl-3-(4-fluorophenyl)propylamino]ethanol;

1-(4-hydroxyphenyl)-2-[3-(3-nitrophenyl)propylamino]ethanol;

1-(3-hydroxy-2-fluorophenyl)-2-[3-(4-methylsulfonyl)propylamino]ethanol;

1-(4-methoxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol;

1-phenyl-2-[1,1-dimethyl-3-(3-methylsulfonyl-phenyl)propylamino]ethanol;

1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride;

1-(phenyl)-2-[1-methyl-3-(4-nitrophenyl)-propylamino]ethanol;

1-(3-hydroxyphenyl)-2-[1-methyl-3-(4-fluorophenyl)propylamino]ethanolsuccinate;

1-(4-hydroxyphenyl)-2-[1-methyl-1-ethyl-3-(4-aminocarbonylphenyl)propylamino]ethanol;

1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-phenylpropylamino]ethanolhydrobromide; and

d-1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-(4-hydroxyphenyl)propylamino]ethanol.

The method of promoting growth and improving leanness and feedefficiency provided by this invention is practiced by administering aneffective amount of a compound defined above to a warm-blooded animalthat receives a nutritionally adequate diet. The method generally willbe practiced on domesticated animals raised for human meat consumption,for example grower/finisher swine, poultry, ruminants and the like. In apreferred embodiment, the growth of pigs, chickens and turkeys ispromoted employing a β-phenethanolamine. Another preferred embodiment ispracticed in ruminants such as cattle, sheep and goats. The method ofimproving leanness is not limited to meat producing animals, and can bepracticed on other warm-blooded animals, including dogs and cats. Thislatter embodiment is particularly useful when it is desired to maintainmature animals in a relatively lean physical state.

The method of the invention is preferably practiced by orallyadministering an effective amount of a β-phenethanolamine to an animal.Other routes of administration can be employed, for instanceintramuscular or intravenious injection; however, such routes are lesspractical. The amount to be administered to an animal is an amount thatis effective in causing a promotion of growth, or an improvement in theefficiency of utilization of food, or an improvement in carcass qualityof the animal, for instance in the form of less fatty tissue andimproved leanness. The effective amount to be administered will varysomewhat depending upon the particular animal species being treated andthe particular active ingredient employed, but generally will be fromabout 1 to about 1000 parts per million (ppm) of total daily feedintake. Such amount will provide a dosage of about 0.05 to about 50mg/kg. A preferred embodiment employs about 1 to about 200 ppm, and morepreferably from about 5 to about 100 ppm. A typical amount of activeingredient to be administered to swine will be from about 5 to about 40ppm. For example, when practicing the method in animals such asruminants or swine, the compound will be added to the daily feed rationat about 5 to about 100 parts per million of the daily feed ration.

For oral administration, the active β-phenethanolamine is preferablyadmixed with suitable carriers or diluents commonly employed in animalhusbandry. Animal feedstuffs comprising a β-phenethanolamine growthpromoter as defined herein are provided as a further embodiment of thisinvention. Typical carriers and diluents commonly employed in suchfeedstuffs include corn meal, soybean meal, alfalfa meal, rice hulls,soybean mill run, cottonseed oil meal, bone meal, ground corn, corncobmeal, sodium chloride, urea, cane molasses and the like. Such carrierspromote a uniform distribution of the active ingredient in the finishedfeed ration into which such compositions are added, thereby ensuringproper distribution of the active ingredient throughout the feed. Thefeedstuff composition provided by the invention will contain about 5 toabout 95 percent by weight of active ingredient, and more typicallyabout 10 to about 50 percent by weight. As already noted, the acidaddition salts of the active phenethanolamines are generally preferredfor oral administration, and are thus the preferred form of activeingredient for the feedstuff compositions of the invention.

While the preferred method for orally administering the growth promotersis via the daily feed rations, the compounds can be incorporated intosalt blocks and mineral licks, as well as being added directly todrinking water for convenient oral consumption. The compounds canadditionally be formulated with polymorphous materials, waxes and thelike for long-term controlled release, and administered to an animal asa bolus or tablet only as needed to maintain the desired daily payout ofactive ingredient.

For parenteral administration, the β-phenethanolamines can be admixedwith conventional carriers such as corn oil, sesame oil, carbowax,calcium stearate and the like. Such formulations can be molded intopellets and administered as an injection or as a slow-releasesubcutaneous implant. Such administrations can be made as often asneeded to ensure the proper dosing of active ingredient to obtain thedesired rate of growth promotion and improvement in leanness and feedefficiency.

While the compounds described herein are effective in promoting averagedaily weight gain and improving feed efficiency in animals, they alsocause observable improvement in the quality of the meat produced. Forexample, the compounds appear to mobilize free fatty acids from fattytissue and depress the deposition of fat as the animals gain weight.This reduction of fat is beneficial since the animal being treatedaccording to the invention gains weight in the form of more useable leanmeat, thereby reducing waste and improving the value of the animal thustreated. Also, mature animals that are not subject to additional weightgain can be maintained in a desirably lean form by administering acompound as described herein.

The practice of the present invention is more fully illustrated by thefollowing detailed examples.

EXAMPLE 1 Preparation of d1-4-(benzyloxy)mandelic acid

A solution of 5.0 g of d1-4-hydroxy mandelic acid, 11.0 g of benzylchloride and 10.0 g of potassium carbonate in 50 ml of methanol washeated to reflux and stirred for seventy-two hours. The reaction mixturewas cooled to room temperature and diluted with 50 ml of water. Theaqueous solution was washed twice with 50 ml portions of benzene, andthen was acidified with concentrated hydrochloric acid. The aqueous acidsolution was extracted three times with 50 ml portions of ethyl acetate.The organic extracts were combined, washed with water and with saturatedsodium chloride solution and dried. Removal of the solvent byevaporation under reduced pressure provided 5.7 g of a solid which wasthen recrystallized from 300 ml of toluene to afford 5.33 g ofd1-4-(benzyloxy)mandelic acid. M.P. 153°-155° C.

Analysis calc. for C₁₅ H₁₄ O₄ Theory: C, 69.76; H, 5.46; Found: C,69.96; H, 5.33.

EXAMPLE 2 Resolution of d1-4-(benzyloxy)mandelic Acid to ProvideR(-)-(4-benzyloxy)mandelic Acid

To a stirred solution of 185.6 g of d1-4-benzyloxy)mandelic acid in 2500ml of ethyl acetate at 80° C. was added in one portion 43.6 g ofR(+)-α-methyl-benzylamine. The reaction mixture was cooled to roomtemperature, and the precipitated solid which had formed was collectedby filtration and washed with fresh ethyl acetate. The solid wasrecrystallized twice from a solution of ninety percent ethanol in waterto provide 91.4 g of the R(+)-α-methylbenzylamine salt ofR(-)-4-(benzyloxy)mandelic acid. M.P. 208.5°-209.5° C. [α]_(D) -38.6°,[α]₃₆₅ -155.3° (MeOH)

Analysis calc. for C₂₃ H₂₅ NO₄ Theory: C, 72.80; H, 6.64; N, 3.69; Found: C, 72.95; H, 6.83; N, 3.95.

To a stirred suspension of 91.4 g of the above-named salt in 2000 ml ofethyl acetate was added 150 ml of ten percent aqueous hydrochloric acidsolution. The aqueous acid solution was separated, and the organic layerwashed with water and dried. Removal of the solvent by evaporation underreduced pressure afforded 54.5 g of R(-)-4-(benzyloxy)mandelic acid, ie.R(-) -2-(4-benzyloxyphenyl)-2-hydroxyacetic acid. M.P. 155°-161° C.[α]_(D) -102.2°; [α]₃₆₅ -410.6° (MeOH)

Analysis calc. for C₁₅ H₁₄ O₄ Theory: C, 69.76; H, 5.46; Found: C,69.67; H, 5.41.

EXAMPLE 3 Preparation of d1-1-methyl-3-(4-benzyloxyphenyl)propylamine

A solution of 40.0 g of methyl 2-(4-benzyloxyphenyl)ethyl ketone and 160ml of anhydrous ammonia in 300 ml of ethanol was heated at 75° C. andstirred for two hours. After cooling the reaction mixture to roomtemperature, 4.0 g of Raney nickel was added in one portion, and thereaction mixture then was stirred at 25° C. for twelve hours under ahydrogen atmosphere at 300 psi. The reaction mixture next was filteredand the filtrate was concentrated by evaporation of the solvent underreduced pressure to provide an oil. The oil was dissolved in 120 ml of3N hydrochloric acid, from which the product as a hydrochloride saltprecipitated. The salt so formed was collected by filtration andrecrystallized from methanol and toluene to provide 36.2 g ofd1-1-methyl-3-(4-benzyloxyphenyl)propylaminium chloride. M.P. 195-197.5°C.

EXAMPLE 4 Resolution of d1-1-methyl-3-(4-benzyloxyphenyl)propylamine toprovide R-(-)-1-methyl-3-(4-benzyloxyphenyl)propylamine

A solution of 629.3 g of d1-1-methyl-3-(4-benzyloxyphenyl)propylaminiumchloride was converted to the free amine by reaction with 95 g of sodiumhydroxide in 400 ml of water. The free amine was then dissolved in 2000ml of methylene chloride and added to a solution of 328 g ofD-(-)-mandelic acid in 1000 ml of methanol. The mandelic acid salt ofthe free amine precipitated out of solution and was recrystallized threetimes from methanol to provide 322 g of the R-mandelic acid salt ofR-1-methyl-3-(4-benzyloxyphenyl)propylamine. M.P 166°-167° C. [α]_(D)-30°, [α]₃₆₅ -119° (MeOH).

The salt so formed was converted toR-1-methyl-3-(4-benzyloxyphenyl)propylamine as the free base by reactionwith aqueous sodium hydroxide.

EXAMPLE 5R,R-N-[2-(4-Benzyloxyphenyl)-2-hydroxy-1-oxoethyl]-1-methyl-3-(4-benzyloxyphenyl)propylamine

A solution of 93.9 g of R-1-methyl-3-(4-benzyloxyphenyl)propylamine in500 ml of N,N-dimethylformamide containing 63.0 g of1-hydroxybenzotriazole and 104.6 g ofR-2-(4-benzyloxyphenyl)-2-hydroxyacetic acid was cooled to 0° C. andstirred while a solution of 83.6 g of N,N'-dicyclohexylcarbodiimide in300 ml of dimethylformamide was added dropwise over one hour. Thereaction mixture was stirred for twelve hours at 3° C. and then wasdiluted with 10 ml of water, stirred for an additional hour, and thencooled to -30° C. in an ice-acetone bath. The reaction mixture wasfiltered to remove dicyclohexylurea, and then the filtrate wasconcentrated by evaporation of the solvent under reduced pressure. Theconcentrated solution was diluted with ethyl acetate and washed withsaturated aqueous sodium carbonate solution, with water, with 300 ml of1N hydrochloric acid, and again with water. The organic layer was driedand the solvent was removed by evaporation under reduced pressure toprovide the product as a white solid. The solid was recrystallized oncefrom acetonitrile and again from methanol to provide 159.7 g ofR,R-N-[2-(4-benzyloxyphenyl)-2-hydroxy-1-oxoethyl]-1-methyl-3-(4-benzyloxyphenyl)propylamine.M.P. 145°-148° C. [α]_(D) -15.9°, [α]₃₆₅ -50.1° (MeOH).

Analysis calc for C₃₂ H₃₃ NO₄ Theory: C, 77.55; H, 6.71; N, 2.83; Found:C, 77.04; H, 6.84; N, 2.53.

EXAMPLE 6R,R-N-[2-(4-Benzyloxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-benzyloxyphenyl)propylamine

To a stirred solution of 10.0 g ofR,R-N-[2-(4-benzyloxyphenyl)-2-hydroxy-1-oxoethyl]-1-methyl-3-(4-benzyloxyphenyl)propylaminein 500 ml of freshly distilled tetrahydrofuran under a nitrogen gasatmosphere was added dropwise over thirty minutes 41 ml of 2 molarborane-dimethyl sulfide complex in tetrahydrofuran. The reaction mixturewas stirred at 25° C. for twenty hours, and then was heated to refluxand stirred for an additional three hours. After cooling the reactionmixture to 25° C. and stirring for another eighteen hours, the excessborane was decomposed by the slow portion-wise addition of 400 ml ofmethanol. The solvent was then removed from the reaction mixture byevaporation under reduced pressure to provide the product as an oil. Theoil so formed was dissolved in 250 ml of hot methanol, and afterconcentrating the volume to 125 ml, the product began crystallizing outof solution. The crystalline product was collected by filtration andrecrystallized twice from methanol to provide 6.65 g ofR,R-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-benzyloxyphenyl)propylamine.M.P. 119°-123.5° C.

The amine so formed was dissolved in methanol and added to a solution ofethereal hydrogen chloride, thereby providing 6.49 g ofR,R-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-benzyloxyphenyl)propylaminiumchloride. M.P. 214.5°-216° C. [α]_(D) -13.4°, [α]₃₆₅ -30.2° (MeOH).

Analysis calc. for C₃₂ H₃₆ NO₃ Cl Theory: C, 74.19; H, 7.00; N, 2.70;Cl, 6.84; Found: C, 74.20; H, 6.98; N, 2.65; Cl, 6.63.

EXAMPLE 7R,R-1-(4-Hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride, also named asR,R-N-[2-(4-Hydroxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-hydroxyphenyl)propylaminiumchloride

A mixture of 51.6 g ofR,R-N-[2-(4-benzyloxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-benzyloxyphenyl)propylaminiumchloride and 5.0 g of Raney nickel in 2 liters of ethanol and 2 litersof ethyl acetate was stirred at 25° C. for four and one-half hours undera hydrogen atmosphere of 60 psi. The reaction mixture was then filteredto remove the residual Raney nickel, and the filtrate was concentratedto an oil by evaporation of the solvent under reduced pressure, and theoil was crystallized from fresh ethanol and diethyl ether to provide29.8 g ofR,R-N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-1-methyl-3-(4-hydroxyphenyl)propylaminiumchloride. M.P. 176°-176.5° C. (dec.) [α]_(D) -22.7°, [α]₃₆₅ -71.2° (3.7mg/ml MeOH).

Analysis calc. for C₁₈ H₂₄ NO₃ Cl Theory: C, 63.99; H, 7.16; N, 4.15;Found: C, 63.70; H, 7.26; N, 4.32.

EXAMPLE 8

As pointed out above, a preferred embodiment of this invention employs amixture of all four optical isomers of the compound of Example 7. Thisracemic mixture can be prepared by the method described above byreaction of d1-4-(benzoyloxy)mandelic acid withd1-1-methyl-3-(4-benzyloxyphenyl)propylamine in the presence of DCC togive racemic1-(4-benzyloxyphenyl)-2-oxo-2-[1-methyl-3-(4-benzyloxyphenyl)propylamino]ethanol.Reduction of the latter compound and subsequent removal of the benzylgroups provides racemic1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol.This compound is more preferably prepared by the following procedure.

A solution of 32.8 g. (0.2 m) of methyl 2-(4-hydroxyphenyl)ethyl ketoneand 42.6 g. (0.2 m) of 1-(4-hydroxyphenyl)-2-aminoethanol in 380 ml. ofethanol containing 3.8 g. of five percent palladium on carbon wasstirred for sixteen hours at 60° C. under hydrogen at 55 psi. Thereaction mixture was then filtered, and the filtrate was diluted byaddition of 350 ml. of water. The aqueous mixture was concentrated to avolume of about 400 ml., and then washed with dichloromethane. Theaqueous mixture was acidified by addition of 50 ml. of conc.hydrochloric acid. After standing at room temperature for two hours, theaqueous acid mixture was filtered and the filter cake was washed with 40ml. of ice water and dried at 50° C. in vacuum to provide 47 g. of1-(4-hydroxyphenyl-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride. M.P. 124°-129° C.

Analysis calc. for C₁₈ H₂₄ NO₃ Cl Theory: C, 63.99; H, 7.16; N, 4.15;Cl, 10.49. Found: C, 63.77; H, 6.80; N, 3.91; Cl, 10.68.

¹³ C NMR studies demonstrated the product to be comprised of 51% RR,SSdiastereamer and 49% RS,SR diastereomer.

EXAMPLE 9 1-Phenyl-2-[1-methyl-3-(4-nitrophenyl)propylamino]ethanol

A solution of 5.0 g. (25.9 mM) of 2-amino-1-phenylethanol and 3.55 g.(25.9 mM) of methyl 2-(4-nitrophenyl)ethyl ketone in 60 ml. of toluenecontaining 10 mg. of para-toluenesulfonic acid was heated at reflux forsix hours in a flask equipped with a Dean-Stark trap. The water thatformed during the reaction was removed via the trap, and then thereaction mixture was cooled to room temperature and concentrated todryness by evaporation of the solvent under reduced pressure. The solidproduct that remained was dissolved in 50 ml. of tetrahydrofuran and thesolution was heated to reflux. A solution of 13.5 ml. of 2Nborane-methyl sulfide complex in tetrahydrofuran was then added dropwiseto the reaction mixture, and the mixture was refluxed for an additionalninety minutes. After cooling the reaction mixture to room temperature,it was diluted by addition of diethyl ether saturated with hydrogenchloride. The precipitate that formed was collected by filtration andcrystallized from ethanol and diethyl ether to give 3.29 g. of1-phenyl-2-[1-methyl-3-(4-nitrophenyl)-propylamino]ethanolhydrochloride. M.P. 203°-213° C.

Analysis calc. for C₁₈ H₂₃ ClN₂ O₃ Theory: C, 61.62; H, 6.61; N, 7.98;Cl, 10.11. Found: C, 61.76; H, 6.62; N, 7.76; Cl, 10.13.

EXAMPLE 101-(4-Hydroxyphenyl)-2-[1,1-dimethyl-3-phenylpropylamino]ethanol

A solution of 32.6 g. (0.2 m) of 1,1-dimethyl-3-phenylpropylamine and22.9 g. (0.1 m) of 2-(4-methoxyphenyl)-2-oxoethyl bromide in 75 ml. oftetrahydrofuran was heated at reflux for thirty-six hours. The reactionmixture was then cooled and added to 2 liters of diethyl ether. Theprecipitate was removed by filtration, and the filtrate was acidifiedwith hydrobromic acid to give 18.15 g. of1-(4-methoxyphenyl)-1-oxo-2-(1,1-dimethyl-3-phenylpropylamino)ethanehydrobromide. M.P. 174°-178° C.

The compound thus formed was dissolved in 85 ml. of glacial acetic acidcontaining 35 ml. of hydrobromic acid, and the solution was heated atreflux for nine hours. The solution was then cooled and the solvent wasremoved by evaporation to provide, following crystallization fromethanol and diethyl ether, 7.8 g. of1-(4-hydroxyphenyl)-1-oxo-2-(1,1-dimethyl-3-phenylpropylamino)ethanehydrobromide. M.P. 228°-230° C.

Catalytic hydrogenation of 5.0 g. of the compound from above in 44 ml.of ethanol containing 1.25 g. of five percent palladium on carbonafforded, following crystallization from acetone and diethyl ether, 2.3g. of 1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-phenylpropylamino)ethanolhydrobromide. M.P. 168°-170° C.

Analysis calc. for C₁₉ H₂₆ BrNO₂ Theory: C, 60.00; H, 6.89; N, 3.68.Found: C, 60.28; H, 6.67; N, 3.62.

EXAMPLE 111-(3-Hydroxyphenyl)-2-[1,1-dimethyl-3-(4-fluorophenyl)propylamino]ethanol

To a stirred solution of 67.2 g. (0.22M) of2-(3-benzyloxyphenyl)-2-oxoethyl bromide in 200 ml. of acetonitrile wasadded a solution of 54.3 g. (0.20M) ofN-benzyl-1,1-dimethyl-3-(4-fluorophenyl)propylamine in 600 ml. ofacetonitrile containing 42 ml. (0.22M) of diisopropylethylamine. Thereaction mixture was stirred for about six hours at reflux, and then wascooled and stored at room temperature for forty-eight hours. Thereaction mixture was next diluted by addition of aqueous sodiumhydroxide, and the organic solvents were removed by evaporation underreduced pressure. The aqueous alkaline mixture was extracted with ethylacetate, which was then washed with water, dried, and concentrated todryness to give an oil. The oil was dissolved in ethanol and diethylether and converted to the hydrochloride salt by addition of excesshydrogen chloride. The precipitated solid was collected by filtrationand recrystallized from ethyl acetate to give 51.3 g. of1-(3-benzyloxyphenyl)-1-oxo-2-[(N-benzyl)-1,1-dimethyl-3-(4-fluorophenyl)-propylamino]ethanehydrochloride. M.P. 137°-145° C.

The compound thus prepared was reduced by reaction with 16 g. of sodiumborohydride in ethanol. Isolation of the product, followed by conversionto the hydrochloride salt and crystallization from diethyl etherafforded 55.0 g. of1-(3-benzyloxyphenyl)-2-[(N-benzyl)-1,1-dimethyl-3-(4-fluorophenyl)propylamino]ethanol hydrochloride. M.P. 186.5°-191° C.

A solution of 10.0 g. of the product thus produced in 200 ml. of ethanolcontaining 3.0 g. of Raney Nickel was shaken for two hours at 25° C.under hydrogen at 44 psi. The reaction mixture was then filtered, andthe solvent was removed from the filtrate by evaporation under reducedpressure to give a white solid. The solid was triturated with ethylacetate and air dried to provide 5.9 g. of1-(3-hydroxyphenyl)-2-[1,1-dimethyl-3-(4-fluorophenyl)propylamino]ethanolhydrochloride. M.P. 196.5°-198.5° C.

Analysis calc. for C₁₉ H₂₅ ClFNO₂ Theory: C, 64.49; H, 7.12; N, 3.96;Cl, 10.02. Found: C, 64.29; H, 6.97; N, 4.06; Cl, 9.89.

EXAMPLE 121-(4-Hydroxyphenyl)-2-[1,1-dimethyl-3-(4-aminocarbonylphenyl)propylamino]ethanol

A suspension of 10.0 g. (50 mM) of1,1-dimethyl-3-(4-aminocarbonylphenyl)propylamine and 15.0 g. (50 mM) of1-(4-benzyloxyphenyl)-1-oxoethyl bromide in 1000 ml. of acetonitrilecontaining 32.0 g. (0.3M) of sodium carbonate and 100 ml. of water wasstirred for one hour at 25° C. The precipitate that formed was collectedby filtration, washed with water and with diethyl ether, and air driedto provide 8.0 g. of1-(4-benzyloxyphenyl)-1-oxo-2-[1,1-dimethyl-3-(4-aminocarbonylphenyl)propylamino]ethane.M.P. 184°-187° C. This product was converted to the hydrochloride saltby reaction with hydrogen chloride in diethyl ether. M.P. 219°-224° C.

The compound thus prepared was reacted with sodium borohydride inmethanol to provide, following conversion to the hydrochloride salt andcrystallization from methanol and diethyl ether, 5.8 g. of1-(4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-aminocarbonylphenyl)propylamino]ethanolhydrochloride. M.P. 141°-143° C.

Reaction of the above compound with hydrogen in the presence of RaneyNickel effected cleavage of the hydroxy protecting group to afford,following crystallization of the hydrochloride salt, 1.3 g. of1-(4-aminocarbonylphenyl)propylamino]ethanol hydrochloride. M.P. 185° C.(dec.)

Analysis calc. for C₂₀ H₂₇ ClN₂ O₃ Theory: C, 63.40; H, 7.18; N, 7.39;Cl, 9.36. Found: C, 63.26; H,.7.01; N, 7.45; Cl, 9.42.

The compounds of Examples 13 and 14 were prepared by the generalprocedure of Example 12.

EXAMPLE 13 1-(27Fluorophenyl)-2-[1,1-dimethyl-3-(₄-aminocarbonylphenyl)propylamino]ethanol hydrochloride

M.P. 227°-230° C.

EXAMPLE 141-(3-Hydroxyphenyl)-2-[1,1-dimethyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrobromide

M.P. 161°-165 ° C.

EXAMPLE 151-Phenyl-2-[1-methyl-3-(4-methylsulfonylphenyl)propylamino]ethanolhydrochloride

Methyl 2-(4-methylthiophenyl)ethyl ketone was oxidized by reaction withm-chloroperbenzoic acid to give methyl 2-(4-methylsulfonylphenyl)ethylketone. A solution of 6.73 g. of 2-amino-1-phenylethanol and 11.10 g. ofmethyl 2-(4-methylsulfonylphenyl)ethyl ketone in 500 ml. of toluenecontaining 200 mg. of p-toluenesulfonic acid was heated at reflux fortwenty-four hours. The reaction mixture was cooled and the solvent wasremoved by evaporation to give the Schiff base1-phenyl-2-[1-methyl-3-(4-methylsulfonylphenyl)propylimino]ethanol. TheSchiff base thus prepared was reacted with 3.7 g. of sodium borohydridein 500 ml. of ethanol at 0° C. for sixteen hours. The reaction mixturewas diluted by addition of 50 ml. of acetone and 20 ml. of 3Nhydrochloric acid. The mixture was concentrated to an oil by evaporationof the solvent. The oil crystallized upon standing at room temperature.Recrystallization of the product from 200 ml. of hot ethanol afforded8.96 g. (48% yield) of1-phenyl-2-[1-methyl-3-(4-methylsulfonylphenyl)propylamino]ethanolhydrochloride. M.P. 164°-170° C.

Analysis calc. for C₁₉ H₂₆ ClNO₃ S Theory: C, 59.44; H, 6.83; N, 3.65;Cl, 9.23; S, 8.35. Found: C, 59.28; H, 6.57; N, 3.70; Cl, 9.36; S, 8.11.

EXAMPLE 16

    ______________________________________                                        Premix for Chickens                                                           Ingredient          % by weight                                               ______________________________________                                        1-(4-hydroxyphenyl)-2-[1,1-                                                                       25                                                        dimethyl-3-phenylpropylamino]-                                                ethanol succinate                                                             Ground Corn         74                                                        Sodium Chloride     1                                                                             100                                                       ______________________________________                                    

EXAMPLE 17

    ______________________________________                                        Premix for ruminants                                                          Ingredient          % by weight                                               ______________________________________                                        1-(2-fluorophenyl)-2-[1,1-                                                                        30                                                        dimethyl-3-(4-aminocarbonyl-                                                  phenyl)propylamino]ethanol                                                    Ground yellow corn  60                                                        Alfalfa meal        10                                                                            100                                                       ______________________________________                                    

EXAMPLE 18

    ______________________________________                                        Premix for Swine                                                              Ingredient            % by weight                                             ______________________________________                                        1-(4-hydroxyphenyl)-2-[1-methyl-                                                                    10                                                      3-(4-hydroxyphenyl)propylamino]-                                              ethanol hydrochloride                                                         Soybean mill run      88                                                      Mineral oil           2                                                                             100                                                     ______________________________________                                    

The above ingredients are blended to uniformity to provide a dryflowable premix that can be admixed with a typical animal feed ration ata rate to provide about 20 ppm of active ingredient in the final feedration. For example, the premix can be added to the following swinegrower ration for convenient oral administration of theβ-phenethanolamine to swine.

    ______________________________________                                        Ingredient           % by weight                                                                              lbs/Ton                                       ______________________________________                                        Corn, yellow, ground 76.70      1534                                          Soybean Oil Meal,    19.35      387                                           solvent extracted, dehulled                                                   Calcium Carbonate    1.20       24                                            Dicalcium Phosphate, feed grade                                                                    1.20       24                                            Salt (sodium chloride)                                                                             0.50       10                                            Trace mineral premix, AN-03.sup.1                                                                  0.10       2                                             Swine Vitamin Premix, SW-03.sup.2                                                                  0.65       13                                            Vitamin A Premix, 3M USP units/lb..sup.3                                                           0.05       1                                             Methionine Hydroxy Analogue, 93%                                                                   0.20       4                                             Selenium Premix.sup.4                                                                              0.005      1                                                                  100.00     2000                                          ______________________________________                                         .sup.1 Each Kg of premix contains: 50 g. manganese as manganese sulfate;      100 g. zinc as zinc carbonate; 50 g. iron as ferrous sulfate; 5 g. copper     as copper oxide; 1.5 g. iodine as potassium iodide and 150 g. maximum and     130 g. minimum calcium as calcium carbonate.                                  .sup.2 Each Kg of premix contains: 77,161 IU Vitamin D.sub.2 ; 2,205 IU       Vitamin E; 411 mg. riboflavin; 1,620 mg. pantothenic acid; 2,205 mg.          niacin; 4.4 mg. Vitamin B.sub.12 ; 441 mg. Vitamin K; 19,180 mg. choline;     110 mg. folic acid; 165 mg. pyridoxine; 110 mg. thiamine; 22 mg. biotin.      .sup.3 Each Kg of premix contains 6,613,800 IU Vitamin A.                     .sup.4 Each Kg of premix contains 200 mg. of selenium as sodium selenite.

EXAMPLE 19

    ______________________________________                                        Feed Ration for Lambs                                                         Ingredient           Percent  lbs/T                                           ______________________________________                                        Yellow corn          61.00    1220.0                                          Corn cobs            20.00    400.0                                           Alfalfa Meal, dehydrated                                                                           5.40     108.0                                           Soybean oil meal     8.00     160.0                                           Urea, feed grade     0.50     10.0                                            Molasses, cane       3.00     60.0                                            Dicalcium phosphate  0.43     8.6                                             Salt                 0.30     6.0                                             Calcium carbonate    0.14     2.3                                             Trace mineral premix.sup.1                                                                         0.03     0.6                                             Vitamin A + D.sub.3 Premix.sup.2                                                                   0.10     2.0                                             Vitamin E Premix.sup.3                                                                             0.10     2.0                                             1-(4-Hydroxyphenyl)-2-(1,1-                                                                        1.00     20.0                                            dimethyl-3-phenylpropylamino)-                                                ethanol                                                                                            100.00   2000.0                                          ______________________________________                                         .sup.1 Trace mineral premix contains: 2.5% manganese as manganese oxide,      0.07% iodine as potassium iodide, 0.3% cobalt as cobalt carbonate, 0.5%       copper as copper oxide, and 20.0% zinc as zinc sulfate.                       .sup.2 Each pound of vitamin A and D.sub.3 premix contains 2,000,000 USP      units Vitamin A and 225,750 USP units Vitamin D.sub.3.                        .sup.3 Each pound of Vitamin E premix contains 20,000 IU Vitamin E.      

The compounds to be employed in the method of this invention havedemonstrated efficacy in animal tests designed to establish beneficialnutritional effects. In one test designed to show lipolytic activity,normal swine, either barrows or gilts, were employed to analyze theeffect of compounds on blood glucose, insulin, and non-esterified fattyacids (NEFA).

Test animals were maintained in metabolism crates, and following aperiod of adaptation, catheters were placed in their femoral veins.Prior to administration of the test compounds, all animals were fastedfor a period of forty hours. Such fasting causes an elevation of NEFA'sin the blood. On the day of the test, all animals were fed a normal feedration, and one group of animals were held as controls while anothergroup of animals received a test compound. The test compounds wereadministered at 200 mcg/kg intravenously, or orally at 1 mg/kg. Bloodsamples were taken from each animal immediately prior to treatment andthen at one hour intervals for a period of six hours followingtreatment. The blood plasma was analyzed for glucose, insulin and NEFAcontent.

When the fasted pigs were fed the normal feed ration without a testcompound, the NEFA levels in the blood drop dramatically and remainedlow. A β-phenethanolamine as defined herein caused either an elevationin NEFA's, or inhibited the drop in NEFA's. Blood levels of glucose andinsulin were also elevated with the β-phenethanolamines.

The following Table presents the lipolytic activity of several preferredβ-phenethanolamines when evaluated according to the test describedabove. The results are averages of several tests.

                  TABLE I                                                         ______________________________________                                        Lipolytic Activity (increase in NEFA's)                                        ##STR2##                                                                                                     % increase                                                                            % increase                                                            in NEFA's                                                                             in glucose                                                            over    over                                  R.sup.1                                                                              R.sup.2                                                                             R.sup.3                                                                              R.sup.4                                                                            R.sup.5                                                                              control control                               ______________________________________                                        H      H     H      CH.sub.3                                                                           SO.sub.2 CH.sub.3                                                                    131     9                                     p-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           H      445     48                                    m-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           H      71      31                                    m-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           F      28      72                                    p-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           OH     141     35                                    p-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           CONH.sub.2                                                                           18      169                                   m-OH   H     CH.sub.3                                                                             CH.sub.3                                                                           OH     68      40                                    H      H     H      H    NO.sub.2                                                                             199     7                                     p-OCH.sub.3                                                                          H     CH.sub.3                                                                             CH.sub.3                                                                           H      84      25                                    p-OCH.sub.3                                                                          H     CH.sub.3                                                                             CH.sub.3                                                                           OH     249     5                                     H      H     H      CH.sub.3                                                                           NO.sub.2                                                                             1458    27                                    ______________________________________                                    

A ten day in vivo study was employed to determine the effect ofβ-phenethanolamines on feed efficiency and rate of growth. In thesestudies, barrows and gilts weighing approximately 60 kg were maintainedin individual pens. Each treatment was replicated six times in randomlyassigned animals, with each test animal forming an experimental unit. Agroup of control animals received a normal swine grower feed rationcomprising the following ingredients:

    ______________________________________                                        Ingredient            % by weight                                             ______________________________________                                        Ground yellow corn    76.70                                                   Soybean oil meal      19.35                                                   Calcium carbonate     1.20                                                    Dicalcium phosphate   1.20                                                    Salt                  0.50                                                    Trace mineral premix  0.10                                                    Swine Vitamin premix  0.65                                                    Vitamin A premix, 3M USP units/lb.                                                                  0.05                                                    Methionine Hydroxy analogue, 93%                                                                    0.20                                                    Selenium premix       0.05                                                                          100.00                                                  ______________________________________                                    

The test animals received the same feed ration plus the test compound.All animals received feed and water ad libitum. All animals were weighedon day 1 and again on day 10, and feed consumption was measured byrecording all feed issued and any remaining feed on day 10. The resultsof two series of this 10 day test for several β-phenethanolamines aregiven in Table II. In the Table, the column labelled "ADG" is theaverage daily weight gain in pounds; "ADF" is the average daily feedconsumption (in pounds) by the test animals; and F/G is the feedefficiency calculated as ADF divided by

                  TABLE II                                                        ______________________________________                                        Growth Promotion and Feed Efficiency                                           ##STR3##                                                                                                  dose                                             R.sup.1    R.sup.2                                                                             R.sup.3                                                                              R.sup.5                                                                            ppm  ADG   ADF   F/G                             ______________________________________                                        Experi-                                                                             Control                       1.60  4.7   2.98                          ment  p-OH     H     H    OH   20   2.19  5.0   2.33                          I     H        H     H    NO.sub.2                                                                           20   1.78  4.22  2.37                          Experi-                                                                             Control                       1.34  4.16  3.22                          ment  p-OH     H     CH.sub.3                                                                           H    20   1.60  4.26  2.66                          II    m-OH     H     CH.sub.3                                                                           F    20   1.52  4.57  3.01                          ______________________________________                                    

The β-phenethanolamines to be employed in the method of this inventioncan be administered in combination with other compounds known to have abeneficial effect upon animals. Typical compounds to be co-administeredwith the β-phenethanolamines include antibiotics, for example any of thetetracyclines, tylosin, penicillins, cephalosporins, polyetherantibiotics, glycopeptides, orthosomycins and related compounds commonlyadministered to swine, poultry, ruminants and the like. A preferredcombination to be employed in the present method is an antibiotic suchas tylosin or a tetracycline, together with1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol.Such combinations will comprise the respective components in a ratio ofabout 1 to about 2 parts by weight of β-phenethanolamine and about 1 toabout 10 parts by weight of the partner component.

In a typical treatment,1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolwas evaluated in a 42-day study employing finishing swine. Eachtreatment was replicated four times, with three pigs per replication.All treatments included a normal feed diet plus tylosin at 40 g/T. Theanimals were tested for growth performance and feed efficiencyenhancement. Carcass quality was determined by analysis for fat andmuscling. The results of the study are given in Table III. Bothβ-phenethanolamine treatments resulted in improved growth performanceand carcasses with less fat and more muscle.

                                      TABLE III                                   __________________________________________________________________________    Growth Promotion, Feed Efficiency                                             and Carcass Quality                                                                              β-phenethanolamine.sup.2                                                 Control.sup.1                                                                      20 g/T                                                                            % change                                                                            40 g/T                                                                            % change                                __________________________________________________________________________    ADG                1.94 2.07                                                                              (6.7) 2.05                                                                              (5.7)                                   ADF                6.28 6.63                                                                              (5.6) 6.64                                                                              (5.7)                                   F/G                3.24 3.20                                                                              (-1.2)                                                                              3.24                                                                              (0)                                     Live Wt. at Slaughter, lb                                                                        217.0                                                                              223.0                                                                             (2.8) 221.0                                                                             (1.8)                                   Chilled Carcass Wt., lb                                                                          154.6                                                                              160.5                                                                             (3.8) 159.8                                                                             (3.4)                                   Fat Depth at 10th Rib, in                                                                        1.15 1.09                                                                              (-5.2)                                                                              1.05                                                                              (-8.7)                                  Loin Eye Area Sp., in                                                                            4.64 4.91                                                                              (5.8) 4.84                                                                              (4.3)                                   Estimated Pounds of Fat Free Muscle.sup.3                                                        74.2 78.8                                                                              (6.1) 78.4                                                                              (5.7)                                   __________________________________________________________________________     .sup.1 all diets contained 40 g/T of tyrosin                                  .sup.2                                                                        1(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]-ethanol        hydrochloride                                                                 .sup.3 A regression equation was employed in arriving at the numerical        predictions of carcass muscle (J. Animal Science, 1977, Vol. 44:8-17).   

The data reported in Table III further demonstrates that theβ-phenethanolamines described herein promote growth, improve feedefficiency and improve leaness.

In a similar study conducted over a 61 day period, a group of controlanimals received a normal daily feed ration with no additive. Anothergroup of animals received the feed ration plus tylosin at 40 g/T, whileanother group received the feed ration plus1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)-propylamino]ethanolhydrochloride (compound A) at 20 g/T. A final group of finishing swinereceived the feed ration plus the combination of 40 g/T of tylosin and20 g/T of the phenethanolamine. The results of this trial are given inTable IV.

                  TABLE IV                                                        ______________________________________                                                                           Tylosin +                                              Control                                                                              Tylosin A       A                                          ______________________________________                                        ADG           1.63     1.64    1.36  1.50                                     ADF           5.64     5.77    5.10  5.38                                     F/G           3.46     3.51    3.77  3.59                                     Slaughter Wt, (lbs)                                                                         210      211     193   201                                      Carcass Wt, (lbs)                                                                           150.3    151.5   140.1 146.3                                    Fat-Depth, 10th                                                                             0.96     0.96    0.80  0.85                                     rib, (in).sup.1                                                               Loin Eye Area (in.sup.2).sup.1                                                              4.60     4.68    4.92  5.00                                     Est. % Muscle.sup.2                                                                         49.2     49.2    51.4  51.2                                     Est. Pounds Muscle.sup.2                                                                    75.3     76.5    74.1  76.8                                     ______________________________________                                         .sup.1 These results are based upon measurement of fat at the 10th rib        after the carcass is split in half across the backbone.                       .sup.2 A regression equation is employed in arriving at the numerical         predictions of carcass muscle (J. Animal Science, 1977, Vol. 44:8-17).   

As in the previous study, both phenethanolamine treatments resulted incarcasses with less fat and more muscle. It should also be noted thatthe estimated amount of carcass muscle produced with the Tylosin +Atreatment was similar to that produced in the control and the Tylosintreatment alone. This result was achieved, however, with less feedconsumption than either the control or the Tylosin treatments.

Additional studies have been carried out to demonstrate the anaboliceffect of β-phenethanolamines in swine. The effect of the compounds onnitrogen retention in finishing barrows was determined. Nitrogenretention is the difference between nitrogen intake and nitrogenexcreted. Increased nitrogen retention is known to be associated withincreased anabolic activity, resulting in improved carcass muscling andleanness.

In a typical study, barrows weighing about 172 pounds (78 Kg) wereorally administered various doses of1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride (Compound A). All animals received water and a constantamount of normal swine feed ration. The results of this study arepresented in Table V, and show that all β-phenethanolamine treatmentsimproved nitrogen retention compared to controls.

                  TABLE V                                                         ______________________________________                                        Nitrogen Retention                                                                            Animals per                                                                              Nitrogen Retained                                  Treatment       treatment  (g/day)                                            ______________________________________                                        Control         6          21.0                                               Compound A (5 g/T)                                                                            3          23.6                                               Compound A (10 g/T)                                                                           3          23.9                                               Compound A (20 g/T)                                                                           3          25.0                                               ______________________________________                                    

As pointed out above, the method of this invention can be practiced withindividual isomers of β-phenethanolamines or with mixtures of isomersand diastereomers. In a study to determine the effect on weight gain andfeed efficacy of various mixtures of diastereomers, barrows initiallyweighing about 177 pounds were fed a normal swine diet plus aβ-phenethanolamine at 20 g/T of feedstuff. Each treatment was replicatedin twelve individually fed animals. The results are presented in TableVI and show that growth performance was improved by bothβ-phenethanolamine treatments with very little change in feed intake.

                  TABLE VI                                                        ______________________________________                                                         Average Daily                                                                             Average Daily                                    Treatment        Feed (lbs)  Gain (lbs)                                       ______________________________________                                        Control          5.89        1.58                                             1-(4-hydroxyphenyl)-2-[1-                                                                      5.94        2.15                                             methyl-3-(4-hydroxyphenyl)-                                                   propylamino]ethanol                                                           hydrochloride                                                                 57.5% RR, SS                                                                  42.5% RS, SR                                                                  1-(4-hydroxyphenyl)-2-[1-                                                                      5.86        1.95                                             methyl-3-(4-hydroxyphenyl)-                                                   propylamino]ethanol                                                           hydrochloride                                                                 47% RR, SS                                                                    53% RS, SR                                                                    ______________________________________                                    

The data in Table VI demonstrates that the method of improving feedefficency and promoting growth can be practiced with any desired mixtureof β-phenethanolamine optical isomers.

The efficacy of the β-phenethanolamines described herein also has beendemonstrated in poultry. In a typical study, broilers that weretwenty-one days old were administered an oral dosing of aβ-phenethanolamine in their normal daily feed ration. All animalsreceived the following broiler finisher ration:

    ______________________________________                                        Ingredients       % by weight                                                                              lbs/T                                            ______________________________________                                        Ground yellow corn                                                                              66.40      1328.00                                          Animal-vegetable fat                                                                            1.53       30.60                                            Corn Glut. meal (60%)                                                                           4.00       80.00                                            Soybean meal (48%)                                                                              19.19      383.80                                           Fish meal-menhaden                                                                              2.50       50.00                                            Dicalcium phosphate                                                                             1.01       34.20                                            Feather meal-Hydr.                                                                              2.50       50.00                                            Ground limestone  0.83       16.60                                            Salt              0.30       6.00                                             Vitamin Premix.sup.1                                                                            0.50       10.00                                            Trace mineral premix.sup.2                                                                      0.10       2.00                                             Methionine Hyd. Anal.                                                                           0.15       3.00                                             Lysine HCl        0.29       5.80                                                               100.00     2000.00                                          ______________________________________                                         .sup.1 Vitamin prenix provides 3000 IU of vitamin A, 900 ICU of vitamin       D.sub.3, 40 mg. of vitamin E, 0.7 mg. of vitamin K, 1000 mg of choline, 7     mg. of niacin, 4 mg of pantothenic acid, 4 mg of riboflavin, 100 mcg of       vitamin B.sub.12, 100 mcg of biotin and 125 mg of ethoxyquin per kg of        complete feed.                                                                .sup.2 Trace mineral premix provides 75 mg of manganese, 50 mg of zinc, 2     mg of iron and 1 mg of iodine per kg of complete feed.                   

Test animals received with the above ration varying doses of1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride (compound A). Each treatment was replicated sixteen times,and the test was terminated when the animals reached fifty-six days ofage. The animals were analyzed for weight gain and feed efficiency. Theresults of this test in broilers is presented in Table VII as meanweight gain and mean feed to gain ratios.

                                      TABLE VII                                   __________________________________________________________________________    Growth Performance of Broilers                                                                         Feed Efficiency                                             Dose Weight Gain  Feed/Gain                                                                            % change                                      Treatment                                                                            (g/T)                                                                              grams                                                                              % improvement                                                                         Ratio  from control                                  __________________________________________________________________________    Control     1473 0       2.336  0                                             Compound A                                                                           10   1585 7.6     2.292  1.9                                           Compound A                                                                           20   1613 9.5     2.298  1.6                                           Compound A                                                                           40   1550 5.2     2.312  1.0                                           Compound A                                                                           80   1669 13.3    2.221  4.9                                           __________________________________________________________________________

The results of this study demonstrate that the β-phenethanolaminesdescribed herein are effective in promoting growth and improving feedefficiency in poultry.

The compounds of the invention also have demonstrated efficacy inruminants. Forty-eight crossbred wether lambs were employed in a testdesigned to show the effects of Compound A(1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanolhydrochloride) at varying doses. Sixteen animals were held as controls,while sixteen received 40 ppm of Compound A, and another sixteenreceived 80 ppm of Compound A. All animals received a normal daily feedration and water ad libitum. Average daily weight gain and average dailyfeed consumption after twenty-eight days is given below in Table VIII.The data demonstrates that a β-phenethanolamine as defined herein iseffective in promoting growth and improving feed efficiency inruminants.

                  TABLE VIII                                                      ______________________________________                                        Growth Performance of Lambs                                                               Dose    ADG        ADF                                            Treatment   (ppm)   (lbs)      (lbs) F/G                                      ______________________________________                                        Control     0       0.414      3.68  8.89                                     Compound A  40      0.418      3.61  8.64                                     Compound A  80      0.472      3.57  7.56                                     ______________________________________                                    

We claim:
 1. A method for promoting the growth of a domesticated warmblooded animal other than a ruminant, swine, or poultry, which comprisesadministering to the animal an effective amount of1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 2. The method of claim 1 wherein theanimal is one raised for human meat consumption.
 3. A method forimproving the feed efficiency of a domesticated warm blooded animalother than a ruminant, swine, or poultry, which comprises administeringto the animal an effective amount of1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 4. The method of claim 3 wherein theanimal is one raised for human meat consumption.
 5. A method forpromoting the growth of a domesticated warm blooded animal whichcomprises administering to the animal an effective amount of a compoundhaving the formula ##STR4## wherein R¹ is hydrogen, hydroxy, ormethoxy;R² is hydrogen or fluoro; R³ is hydrogen or C₁ -C₂ alkyl; R⁴ ishydrogen or methyl; R⁵ is hydrogen, fluoro, nitro, hydroxy, SO₂ CH₃ orCONH₂ ; provided that R¹ is hydrogen only when R⁵ is nitro or SO₂ CH₃,or an acid addition salt thereof; excluding the compounds1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanoland 1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-phenylpropylamino)ethanol andtheir acid addition salts.
 6. The method of claim 5 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 7. The method of claim 5 wherein theanimal is one raised for human meat consumption.
 8. The method of claim7 wherein the animal is a ruminant.
 9. The method of claim 7 wherein theanimal is a swine.
 10. The method of claim 7 wherein the animal ispoultry.
 11. The method of claim 10 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 12. The method of claim 11 wherein thepoultry is a turkey.
 13. The method of claim 11 wherein the poultry is achicken.
 14. A method for improving the efficiency of feed utilizationby a domesticated warm blooded animal which comprises administering aneffective amount of a compound of the formula ##STR5## wherein: R¹ ishydrogen, hydroxy, or methoxy;R² is hydrogen or fluoro; R³ is hydrogenor C_(l) -C₂ alkyl; R⁴ is hydrogen or methyl; R⁵ is hydrogen, fluoro,nitro, hydroxy, SO₂ CH₃ or CONH₂ ; provided that R¹ is hydrogen onlywhen R⁵ is nitro or SO₂ CH₃, or an acid addition salt thereof; excludingthe compounds1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanoland 1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-phenylpropylamino)ethanol andtheir acid addition salts.
 15. The method of claim 14 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 16. The method of claim 14 wherein theanimal is one raised for human meat consumption.
 17. The method of claim16 wherein the animal is a ruminant.
 18. The method of claim 16 whereinthe animal is a swine.
 19. The method of claim 16 wherein the animal ispoultry.
 20. The method of claim 19 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 21. The method of claim 20 wherein thepoultry is a turkey.
 22. The method of claim 20 wherein the poultry is achicken.
 23. A method for improving leanness in a domesticated warmblooded animal which comprises administering to the animal an effectiveamount of a compound of the formula ##STR6## wherein: R¹ is hydrogen,hydroxy, or methoxy;R² is hydrogen or fluoro; R³ is hydrogen or C₁ -C₂alkyl; R⁴ is hydrogen or methyl; R⁵ is hydrogen, fluoro, nitro, hydroxy,SO₂ CH₃ or CONH₂ ; provided that R¹ is hydrogen only when R⁵ is nitro orSO₂ CH₃, or an acid addition salt thereof; excluding the compounds1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanoland 1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-phenylpropylamino)ethanol andtheir acid addition salts.
 24. The method of claim 23 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 25. The method of claim 23 wherein theanimal is one raised for human meat consumption.
 26. The method of claim25 wherein the animal is a ruminant.
 27. The method of claim 25 whereinthe animal is a swine.
 28. The method of claim 25 wherein the animal ispoultry.
 29. The method of claim 28 employing1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt.
 30. The method of claim 23 wherein the animalis a dog.
 31. The method of claim 23 wherein the animal is a cat.
 32. Ananimal feedstuff comprising a β-phenethanolamine of the formula ##STR7##wherein: R¹ is hydrogen, hydroxy, or methoxy;R² is hydrogen or fluoro;R³ is hydrogen or C₁ -C₂ alkyl; R⁴ is hydrogen or methyl; R⁵ ishydrogen, fluoro, nitro, hydroxy, SO₂ CH₃ or CONH₂ ; provided that R¹ ishydrogen only when R⁵ is nitro or SO₂ CH₃, or an acid addition saltthereof; excluding the compound1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-phenylpropylamino)ethanol and itsacid addition salts.
 33. The feedstuff of claim 32 wherein theβ-phenethanolamine is1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 34. The feedstuff of claim 32 whereinthe β-phenethanolamine is1-(4-hydroxyphenyl)-2-(1,1-dimethyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 35. The feedstuff of claim 32containing from about 5 to about 95 percent by weight of theβ-phenethanolamine.
 36. The feedstuff of claim 35 comprising corncobmeal as a carrier.
 37. The feedstuff of claim 36 wherein theβ-phenethanolamine is1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanolor an acid addition salt thereof.
 38. The feedstuff of claim 37 whereinthe β-phenethanolamine is1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanolhydrochloride.